Identification of tissue of origin in carcinoma of unknown primary with a microarray-based gene expression test

De
Monzon,, Medeiros, Fabiola, Lyons-Weiler, Maureen, Henner,

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Carcinomas of unknown primary (CUP) represent approximately 3%-5% of malignant neoplasms. Identifying the tissue of origin (TOO) in these tumors allows for more specific treatment and improves outcomes. However, primary classification remains a challenge in many cases. We evaluated the ability of a microarray-based gene expression test to identify the TOO in tumor specimens from 21 patients with a diagnosis of CUP. Methods The Pathwork ® TOO Test was used to measure gene expression patterns for 1550 genes; these were compared for similarity to patterns from 15 known tissue types. Results The TOO Test yielded a clear single positive call for the primary site in 16 of 21 (76%) specimens and was indeterminate in 5 (24%). The positive results were consistent with clinicopathologic suggestions in 10 of the 16 cases (62%). In the remaining six cases the positive results were considered plausible based on clinical information. Positive calls included colorectal (5), breast (4), ovarian (3), lung (2), and pancreas (2). The TOO Test ruled out an average of 11 primary tissues in each CUP specimen. Conclusion The Pathwork TOO Test reduced diagnostic uncertainty in all CUP cases and could be a valuable addition or alternative to current diagnostic methods for classifying uncertain primary cancers.

Abstract Background:Carcinomas of unknown primary (CUP) represent approximately 3%5% of malignant neoplasms. Identifying the tissue of origin (TOO) in these tumors allows for more specific treatment and improves outcomes. However, primary classification remains a challenge in many cases. We evaluated the ability of a microarraybased gene expression test to identify the TOO in tumor specimens from 21 patients with a diagnosis of CUP. Methods:The Pathwork® TOO Test was used to measure gene expression patterns for 1550 genes; these were compared for similarity to patterns from 15 known tissue types. Results:The TOO Test yielded a clear single positive call for the primary site in 16 of 21 (76%) specimens and was indeterminate in 5 (24%). The positive results were consistent with clinicopathologic suggestions in 10 of the 16 cases (62%). In the remaining six cases the positive results were considered plausible based on clinical information. Positive calls included colorectal (5), breast (4), ovarian (3), lung (2), and pancreas (2). The TOO Test ruled out an average of 11 primary tissues in each CUP specimen. Conclusion:The Pathwork TOO Test reduced diagnostic uncertainty in all CUP cases and could be a valuable addition or alternative to current diagnostic methods for classifying uncertain primary cancers.

Background Patients with carcinoma of unknown primary (CUP) present with metastatic disease for which the tissue of origin (TOO) cannot be identified. About 3%5% of all diagnosed cancers are classified as CUP [14] and an estimated 31,490 new cases of cancer of unspecified pri mary sites were diagnosed in the United States in 2008 [5]. Prognosis of patients with CUP is usually poor with empiric treatment. Median survival is 39 months even with newer combination regimens [4,610]. It has been shown that survival can improve if the primary site is identified and specific therapy is instituted [11,12] as currently recommended in therapeutic guidelines [4,13]. Unfortunately, primary tumor detection remains chal lenging. While serum tumor markers, imaging tests, and immunohistochemistry (IHC) panels can help identify the tissue of origin, the primary site is identified in

fewer than 30% of those who present initially with occult primary tumor [1315]. Furthermore, some posi tive findings can be misleading [2,16]. For example, in three large IHC studies (>50 specimens) of known meta static specimens, IHC findings failed to agree with the site of origin in about one third of cases [1719]. In addition, CUP diagnostic workups today are all too often timeconsuming, expensive, and unsuccessful [13,20]. Recently, gene expression tests to classify tumors by tissue origin have been developed. These tests employ microarrays or realtime reverse transcriptase polymer ase chain reaction (RTPCR) to measure mRNA tran scripts [2129] and one uses a microarray to quantify microRNAs [30]. Thus far, performance of these expres sion tests has been assessed mainly by challenges against panels of tumors from known primary sites; however, the panel composition has varied widely in terms of spe cimen number, specimen handling, tissue types included, number of replicates for each tissue type, and the proportions of metastatic and poorly differentiated